Dataset Information

The In Silico Prediction of Hotspot Residues that Contribute to the Structural Stability of Subunit Interfaces of a Picornavirus Capsid.

ABSTRACT: The assembly of picornavirus capsids proceeds through the stepwise oligomerization of capsid protein subunits and depends on interactions between critical residues known as hotspots. Few studies have described the identification of hotspot residues at the protein subunit interfaces of the picornavirus capsid, some of which could represent novel drug targets. Using a combination of accessible web servers for hotspot prediction, we performed a comprehensive bioinformatic analysis of the hotspot residues at the intraprotomer, interprotomer and interpentamer interfaces of the Theiler's murine encephalomyelitis virus (TMEV) capsid. Significantly, many of the predicted hotspot residues were found to be conserved in representative viruses from different genera, suggesting that the molecular determinants of capsid assembly are conserved across the family. The analysis presented here can be applied to any icosahedral structure and provides a platform for in vitro mutagenesis studies to further investigate the significance of these hotspots in critical stages of the virus life cycle with a view to identify potential targets for antiviral drug design.

SUBMITTER: Upfold N

PROVIDER: S-EPMC7232237 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The In Silico Prediction of Hotspot Residues that Contribute to the Structural Stability of Subunit Interfaces of a Picornavirus Capsid.

Upfold Nicole N Ross Caroline C Tastan Bishop Özlem Ö Knox Caroline C

Viruses 20200331 4

The assembly of picornavirus capsids proceeds through the stepwise oligomerization of capsid protein subunits and depends on interactions between critical residues known as hotspots. Few studies have described the identification of hotspot residues at the protein subunit interfaces of the picornavirus capsid, some of which could represent novel drug targets. Using a combination of accessible web servers for hotspot prediction, we performed a comprehensive bioinformatic analysis of the hotspot re ...[more]

PMID: 32244486

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Project description:The mammalian orthoreovirus (reovirus) outer capsid is composed of 200 ?1-?3 heterohexamers and a maximum of 12 ?1 trimers. During cell entry, ?3 is degraded by luminal or intracellular proteases to generate the infectious subviral particle (ISVP). When ISVP formation is prevented, reovirus fails to establish a productive infection, suggesting proteolytic priming is required for entry. ISVPs are then converted to ISVP*s, which is accompanied by ?1 rearrangements. The ?1 and ?3 proteins confer resistance to inactivating agents; however, neither the impact on capsid properties nor the mechanism (or basis) of inactivation is fully understood. Here, we utilized T1L/T3D M2 and T3D/T1L S4 to investigate the determinants of reovirus stability. Both reassortants encode mismatched subunits. When ?1-?3 were derived from different strains, virions resembled wild-type particles in structure and protease sensitivity. T1L/T3D M2 and T3D/T1L S4 ISVPs were less thermostable than wild-type ISVPs. In contrast, virions were equally susceptible to heating. Virion associated ?1 adopted an ISVP*-like conformation concurrent with inactivation; ?3 preserves infectivity by preventing ?1 rearrangements. Moreover, thermostability was enhanced by a hyperstable variant of ?1. Unlike the outer capsid, the inner capsid (core) was highly resistant to elevated temperatures. The dual layered architecture allowed for differential sensitivity to inactivating agents.IMPORTANCE Nonenveloped and enveloped viruses are exposed to the environment during transmission to a new host. Protein-protein and/or protein-lipid interactions stabilize the particle and protect the viral genome. Mammalian orthoreovirus (reovirus) is composed of two concentric, protein shells. The ?1 and ?3 proteins form the outer capsid; contacts between neighboring subunits are thought to confer resistance to inactivating agents. We further investigated the determinants of reovirus stability. The outer capsid was disrupted concurrent with the loss of infectivity; virion associated ?1 rearranged into an altered conformation. Heat sensitivity was controlled by ?3; however, particle integrity was enhanced by a single ?1 mutation. In contrast, the inner capsid (core) displayed superior resistance to heating. These findings reveal structural components that differentially contribute to reovirus stability.

Dataset Information

The In Silico Prediction of Hotspot Residues that Contribute to the Structural Stability of Subunit Interfaces of a Picornavirus Capsid.

Publications

The In Silico Prediction of Hotspot Residues that Contribute to the Structural Stability of Subunit Interfaces of a Picornavirus Capsid.

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